tbuckley/cabot-search huggingface dataset:
OS02.5.A DEVELOPMENT OF A PATIENT DECISION AID FOR PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA - A CO-CREATION PROCESS
Authors: H Sørensen von Essen, F Rom Poulsen, R Hedegaard Dahlrot, K Piil, K Dahl Steffensen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Patients with high-grade gliomas (HGG) face a difficult decision when the tumor recurs. There are no curable treatments, and all palliative treatment options include risks of complications and adverse effects. In this situation, support is needed for patients to navigate between these trade-offs and make preference-sensitive decisions. Shared decision making (SDM) is an approach where a decision is made in collaboration between a clinician and a patient by combining the clinician’s scientific evidence and knowledge with the patient’s subjective values and preferences. SDM aims to make quality decisions congruent with the individual patient’s informed preferences and to support patients in the decisional process. Patient decision aids (PtDA’s) have proven to be an efficient tool for facilitating SDM. However, there are no PtDA’s available for patients with recurrent HGG. This study aimed to develop a PtDA in a co-creation process with patients with recurrent HGG and family caregivers MATERIAL AND METHODS Based on the International Patient Decision Aids Standards, our team developed a PtDA through an iterative process of drafting and re-drafting. Patients and family caregivers were involved throughout the process as active team members. The PtDA was alpha-tested using structured interviews and the Preparation for Decision Making Scale questionnaire to assess the understandability, acceptability, and perceived usefulness of the PtDA. Data were analyzed using descriptive statistics and a directed content-analysis approach. RESULTS The final draft of the PtDA contained six treatment and care options, including the option of doing nothing. A balanced presentation of benefits and disadvantages was described for each option. In the alpha test, 31 patients with HGG, family caregivers, and clinicians assessed the final draft of the PtDA and found it to be understandable and acceptable. Patients and family caregivers perceived the PtDA to have a higher level of usefulness in supporting and preparing for decision making than did the clinicians (p=0.05). Ten of 11 clinicians were willing to use the PtDA in future consultations. CONCLUSION The PtDA was assessed to be understandable and acceptable by patients, family caregivers, and clinicians. It was perceived to support and prepare patients with recurrent HGG for decision making, and the clinicians were willing to use it in consultations. The involvement of patients and family caregivers as team members added value to the development process and the PtDA. However, the most applicable model of patient involvement in neurooncological research must be further explored to identify the benefits and limitations of approaches.
P11.10.B USEFULNESS OF PHOTODYNAMIC THERAPY (PDT) WITH TALAPORFIN SODIUM FOR GLIOBLASTOMA
Authors: T Sasayama, K Tanaka, H Nagashima, Y Fujita, S Yamanishi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Photodynamic therapy (PDT) with talaporfin sodium uses the toxicity of singlet oxygen generated by a reaction between a photosensitizer in tumor cells and light with a specific wavelength. PDT was introduced in our hospital in April 2017. We retrospectively analyzed the glioblastoma (GBM) patients treated with PDT and compared with the patients who did not receive PDT. MATERIAL AND METHODS From April 2015 to March 2023, total 145 patients with GBM were treated in our hospital. Among them, 90 patients with GBM were performed PDT. Patients of recurrence, IDH mutant, biopsy and no chemo/radiotherapy were excluded. After the tumor had been resected as extensively as possible, the region of probable tumor invasion in the resection cavity were irradiated superficially with a 664-nm diode laser for 180 sec (27 J/cm2) at a power density of 150 mW/cm. The patients’ characteristics, adverse event, changes of the MR image, recurrence pattern, outcome of the patients were analyzed. In addition, survival time of the patients between the PDT group and the non-PDT group was compared. RESULTS A total of 80 GBM patients were analyzed. Forty-four patients received PDT. Gross total resection (GTR), Subtotal resection(STR), and partial resection were performed in 56, 16, and 8 patients, respectively. In the PDT group, 4 patients had adverse event; cyst formation, venous infarction, brain swelling, and delirium. In most of the patients, linear high signals of 5-7 mm on DWI were detected at the surface of the resected cavity and matched the PDT-irradiated area from 1 day after PDT. All hyperintense signal on DWI disappeared in about 30 days without any neurological deterioration. Sixty-seven patients had recurrence (PDT group; 33 cases, non-PDT group; 34 cases). Recurrence pattern of distant/dissemination were significantly increased in the PDT group compared with the non-PDT group. The PDT group tended to have longer survival in both OS (p=0.08) and PFS(p=0.07) than the non-PDT group. In multivariate analysis for OS, age and MGMT promotor methylation were significant prognostic factors, but not PDT. CONCLUSION PDT was safety and useful for GBM. However, the PDT group had significantly more distant/disseminated recurrences than the non-PDT group. We need to analyze more cases to clarify efficacy and recurrence patterns.
OS01.4.A A DETECTABLE ANTITUMOR IMMUNE RESPONSE IS PRESENT IN GLIOMAS, BUT IS PROFOUNDLY DAMPED BY CHEMOTHERAPY
Authors: A Picca, M Baron, K Labrèche, A Bouzidi, A Rousseau, V Morin, F Bielle, M Touat, M Sanson, B Autran
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Until now, immunotherapy has been disappointing in gliomas. Promising results in cancer neoantigen (NeoAg)-directed vaccines have been seen, but final outcomes remain poor. We need a better comprehension of the factors associated with effectively immunogenic NeoAgs along with clinical features that correlate with detectable immune responses. MATERIAL AND METHODS We prospectively enrolled glioma patients from our institution in the IDeATIon project (NCT03706625) exploring tumors occurring in immunosuppressed conditions or in immune-privileged sites such as the CNS. We performed whole exome and RNA sequencing of tumor samples along with patients HLA typing. Using state of the art algorithms and personalized filters, we predicted cancer NeoAg sequences and expression. Peripheral blood mononuclear cells (PBMC) were collected in a subset of patients, and their reactivity to NeoAg-derived peptides was assessed ex vivo using ELISpot assays to validate in silico-predicted immunogenicity. RESULTS We enrolled 36 prospective glioma patients (IDH mutant, n=10; IDH wildtype, n=26). To test the ability of our pipeline to identify the most immunologically relevant NeoAgs among others, we privileged the inclusion of mismatch-repair (MMR)-deficient (MMRd) gliomas (n=21, of which 12 post-temozolomide and 9 de novo), given their expected high NeoAg burden. The median number of predicted immunogenic NeoAgs from 21 patients with both WES and RNASeq data was 274 and was higher for MMRd gliomas (1540 vs. 58, p&amp;lt;0.001). Tumor mutational burden and the number of predicted NeoAgs were correlated (ρ=0.81, p&amp;lt;0.001). Ex vivo PBMC responses were assessed for best ranked peptides (median 48 peptides/patient, range 12-62) in 18 patients (10 MMRd). NeoAg-specific T-cell responses (&amp;gt;50 spot forming units/10e6 PBMC) were detected in 72% (13/18) of patients, including MMRd cases (8/10). All non-responder patients (5/5) were under treatment with cytotoxic chemotherapies (CHT) at the time of blood sampling, compared to 15% (2/13) of responders (p=0.003). Conversely, NeoAg-specific responses were seen in 100% (11/11) of patients not under CHT. CONCLUSION We developed and validated in vitro a robust and reliable pipeline for the identification of effectively immunogenic neoantigens using validated algorithms and personalized filters. Our results suggest that in the absence of CHT, a specific antitumor immune response is present in the majority of gliomas and may represent a therapeutic lever.
P02.22.B CELLULAR COMPOSITION DETERMINED BY STEMNESS MARKERS IN MONOLAYER GLIOBLASTOMA CULTURES IS TUMOR SPECIFIC, HIGHLY DYNAMIC AND RELATED TO TMZ SENSITIVITY
Authors: I S C Verploegh, A de Kroon, F A M Verhoeven, S Loriaux, H e. Hassnaoui, M Lamfers, D Huylebroeck, S Leenstra
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Different models are used to study pathophysiology and potential new therapeutic strategies of glioblastoma (GBM) in vitro. Generally, monolayer cultures are chosen because of their high reproducibility, while spheroid cultures are preferred to better recapitulate tumor heterogeneity and effects of the micro-environment. A common assumption is that monolayer cultures display less plasticity than spheroid cultures. In this study we examine the plasticity of stem cell-like cells in monolayer cultures and their relationship to temozolomide (TMZ) sensitivity. MATERIAL AND METHODS Three patient-derived GBM cultures: one TMZ sensitive, one induced TMZ-resistant and one naturally TMZ-resistant were used. All cultures were sorted in four subpopulations (CD133+/CD44+, CD133+/CD44-, CD133-/CD44+ and CD133-/CD44-) and subsequently cultured. Cellular composition was determined at multiple timepoints by immunofluorescent imaging and FACS-analysis. The effect of seeding density on cellular composition was assessed. Furthermore the effect of original culture composition on sphere forming capacity and TMZ sensitivity was assessed. RESULTS Culture composition was tumor-specific and the pre-sorting composition was acquired within two passages after sorting, irrespective of original subpopulation or sorting density. Even the CD133-/CD44- subpopulation was able to rapidly re-acquire the initial tumor composition. Furthermore, sphere-forming capacity was restored four passages after sorting. Interestingly, cells that were inherently resistant to TMZ expressed higher levels of CD44 than TMZ-sensitive cells. There was no relationship between expression of CD133 and sensitivity to TMZ. Sensitivity to TMZ was similar in all subpopulations four passages after sorting. CONCLUSION Monolayer cultures display rapid plasticity with regard to the expression of the stemness markers CD133 and CD44. Culture composition is tumor specific and inherently programmed in each tumor cell. TMZ sensitivity seems to be mostly related to CD44 expression, and not to CD133 expression. Sphere forming capacity and TMZ sensitivity are restored soon after sorting, even in initially differentiated GBM cells.
P20.13.A AUTOGRAFTED HUMAN CORTICAL SLICE MODEL REVEALS MESENCHYMAL-LIKE TRANSITION IN BRAF-MUTATED GLIOBLASTOMA UNDER TARGETED THERAPY
Authors: J Zhang, K Joseph, J Beck, O Schnell, V M Ravi, D H Heiland
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The emergence of personalized therapy, which targets oncogenic drivers, has provided a novel adjunct to the standard-of-care therapy for glioblastoma, the most common central nervous system malignancy. Among the less frequently observed oncogenic drivers in glioblastoma are mutations in the proto-oncogene B-Raf. Although treatment options for BRAF-mutated malignancies have been extensively investigated, the implications of BRAF and MEK inhibition in gliomas remain ambiguous. In this study, we present a model system designed to predict cellular temporal trajectories, employing human neocortical slice models and patient-derived tumor cells, coupled with spatially resolved and single-cell transcriptomic analyses for comprehensive computational modeling. MATERIAL AND METHODS Non-neoplastic cortical tissue was procured from a BRAF(V600E) mutant glioblastoma patient during surgical intervention. The tissue was sectioned and inoculated with autologous glioblastoma cells to establish an ex-vivo personalized brain slice model. To facilitate adequate tumor growth, slices were cultured for seven days with clinically approved BRAF/MEK inhibitors and respective controls. For high-dimensional analysis, the tumor specimen and slices in all treatment conditions were profiled using live cell imaging, spatially resolved transcriptomics (Visium 10X) and single nucleus RNA-sequencing (10X). Advanced computational modeling techniques, encompassing graph neural networks and single-cell deconvolution, were employed to scrutinize the spatio-temporal evolution of the tumor and its microenvironment. RESULTS Live cell imaging showed varied treatment responses in tumor growth during culture. Immunofluorescence and immunohistochemistry analyses (using NeuN, GFAP, and Iba-1 cell markers) indicated no toxic effects from drug combinations on the tumor microenvironment. Single nucleus profiling revealed a tumoral trajectory towards induction of mesenchymal-like transcriptional programs under BRAF/MEK inhibition along with up-regulation of alternative receptor tyrosine kinases such as HER2/3 and EGFR. Spatial projection of single cell trajectories using cytospace confirmed the escape mechanism of BRAF/MEK inhibition due to acquisition of anti-inflammatory myeloid cells in close proximity to the tumor niches and enhancement of mesenchymal transcriptional programs. In line with the experimental set-up, we observed a rapid progression of the tumor und BRAF/MEK inhibition in the patient. CONCLUSION Our reported model system, employing high-dimensional readouts and advanced computational modeling, showcases a promising avenue to address uncertainties in personalized medicine, emphasizing that conventional oncological drivers may necessitate alternative treatment strategies in central nervous system malignancies.
OS08.5.A UNDERSTANDING THE ASSOCIATION BETWEEN FATIGUE AND COGNITION IN GLIOMA PATIENTS: AN OBSERVATIONAL MULTINATIONAL STUDY
Authors: J G Röttgering, J W Taylor, M Brie, T Luks, S L Hervey-Jumper, S Phan, P M Bracci, E Smith, P C De Witt Hamer, L Douw, C Weyer-Jamora, M Klein
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Both fatigue and cognitive impairment are highly prevalent in individuals with glioma and have been associated with diminished health-related quality of life. Although the two are thought to be related, evidence remains sparse, in part, due to the limited availability of data. Therefore, we aimed to investigate the relationship between fatigue and cognition in adult glioma patients. MATERIAL AND METHODS We analyzed cognitive data from adult patients with diffuse glioma at the University of California San Francisco (UCSF, n=100) and Amsterdam UMC (n=127). Comparable cognitive tests were combined by domain: attention, information processing, mental flexibility, semantic fluency, verbal learning, verbal memory, and visual search. Z-scores of ≤ -1.5 SD were considered impaired. Fatigue was assessed with the Fatigue Symptom Inventory (UCSF) and the Checklist Individual Strength (Amsterdam UMC). Linear mixed models were used to assess associations between cognitive domains and fatigue adjusted for site, grade, histology, sex, radiotherapy, and chemotherapy. Latent profile analysis was used to identify distinct fatigue-cognitive phenotypes. RESULTS UCSF patients were older (50.3 vs. 44.9 years, p=0.002), more likely to have grade 4 tumors (32% vs. 18%, p=0.025), and more years since diagnosis (2.72 vs 1.27, p&amp;lt;0.001). Interestingly, though UCSF patients were more impaired across nearly all cognitive domains, there was no difference in fatigue between institutions (-0.0457 vs. -0.178, p=0.60). Attention and impaired semantic fluency were associated with fatigue severity in univariate models. Using backward selection, the best-fit model included only impaired semantic fluency (estimated effect = 0.35, p= 0.014, r2=0.03). We identified four distinct cognitive phenotypes in the pooled dataset, which validated across sites, though fatigue severity did not contribute to these phenotypes. CONCLUSION Although fatigue and cognitive symptoms can overlap, the association between cognitive impairment and fatigue severity is weak. Interestingly, this important finding was validated across institutions and glioma subtypes. Further study is needed to address questions regarding the longitudinal change of symptoms. Given the limited relational overlap, fatigue and cognitive impairments should both be explicitly assessed and treated with targeted therapies. SUPPORT/DISCLOSURE Stichting Anita Veldman Foundation CCA-2019-2-21; Amsterdam University Fund 4056-2022-7-8; CCA travel grant 2022-10-10; Prins Bernhard Cultuurfondsbeurs 40042576/NOD; R.A. Laan fonds 2022-10-24; The loglio Collective; Sheri Sobrato Brisson Brain Cancer Survivorship Program.
P10.28.B INTERMODEL VARIATION OF BBB PERMEABILITY AFFECTS CNS DRUG DELIVERY IN PDX MODELS OF GBM
Authors: I Ntafoulis, S L W Koolen, C W J den Hollander, E Goedknegt, J Haeck, T V Kers, S Dijkhuizen, V van Dis, T P P van den Bosch, Z Gao, L Mezzanotte, O van Tellingen, C M F Dirven, S Leenstra, M L M Lamfers
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB) and the efflux transporters. Therefore, it is crucial to select drugs able to cross BBB and reach the tumor tissue in therapeutically effective concentrations. In current study, we evaluated the anti-glioma effect of the protein synthesis inhibitor omacetaxine mepesuccinate (OMA) in vitro and its CNS penetrating properties in vivo. MATERIAL AND METHODS The FDA-approved Oncology Drug Set II library was tested on 55 patient-derived GBM cell cultures. We designed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. We developed and characterized 3 orthotopic mouse PDX models in terms of brain vascular integrity, BBB permeability and expression of ABC transporters. The PK profile of omacetaxine was assessed in these orthotopic mouse PDX models. RESULTS In vitro, OMA revealed anti-tumor activity at IC50 values well-below reported Cmax plasma value (Cmax=43nM) in approximately 80% of GBM cultures. Unexpectedly, OMA does not downregulate the expression of its acknowledged target, ribosomal protein 3 (RPL3). In glioma cells while activation of caspase 3/7 activity is linked to its anti-tumor effect. OMA is a substrate for ABCB1 (P-glycoprotein) but not for ABCG2 (BCRP). In vivo, dose escalation showed safety of the drug and OMA was found to reach the brain tumor tissue in concentrations similar or higher to the reported IC50 values in vitro, depending on the PDX model used. No adverse reactions were noted. CONCLUSION OMA is a CNS penetrant drug that reaches the brain tumor tissue in all tested concentrations. The inter-model variation in accumulation of OMA is associated to the extent of BBB disruption of each PDX model. Additional in vivo experiments are ongoing to investigate the therapeutic effect of OMA and longer exposure using in vivo models.
P15.12.A BIUX2X2
Authors: E Gromova, A Smirnova, G Kataeva, N Plakhotina
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain metastases occur in 20-40% of cancer patients. In connection with the development of radiosurgical treatment, the problem of differential diagnosis of continued tumor growth and post-radiation changes becomes relevant. The main method of radiosurgical treatment of secondary lesions is the Gamma-Knife. Positron emission tomography with 11C-Meth and 18F-FET is an important method in monitoring the treatment of patients with secondary brain tumors. MATERIAL AND METHODS We examined 73 patients with brain metastases. Of these, 36.36% were patients with breast cancer, 39.39% were patients with lung cancer, 9.00% were patients with melanoma, 6.06% were patients with kidney cancer, 9.09% were other nosology, which corresponds to the data on the frequency of metastasis to the brain of various types of cancers. All patients underwent MRI with standard sequences (T1, T2, FLAIR, T1+C) and PET-CT with 18F-FET. PET-CT was performed according to the standard protocol: scanning 20 minutes after the INTRODUCTION of the radiopharmaceutical, scanning time 20 minutes. The evaluation of PET images was carried out by a semi-quantitative method - TBR max. RESULTS The mean age of patients with breast cancer was 54.5 ± 10.4, which significantly differs from the mean age of patients with lung cancer (65.9 ± 8.7) and the mean age of patients with other primary cancers (62.8 ± 8, 8) (Kruskal-Wallis test: H(2, N=66)=13.99052 p=.0009). Differences in TBR max and the number of metastases in these groups are not significant, as well as, according to the Kaplan-Meier analysis, differences in the duration of the relapse-free period. However, differences in the duration of the relapse-free period in the groups after a single ( Median, Q1; Q3) (12.9, 10.5; 24.4) or multiple (7.5, 3.5; 10.5) radiosurgical treatment are significant ( Gehan's Wilcoxon Test, Test statistic = 2.063905 p = .03903). Based on the analysis of the data obtained, it was found that the threshold value TBR max &amp;gt;=2.8 in 100% of cases indicates progression, TBR max &amp;lt;=1.7 indicates a stable course. Whereas TBR max in the range from 1.7 to 2.8 (in 33 people from the examined group, i.e. in 50% of all cases) may indicate both progression and post-radiation changes, as well as confirmed positive dynamics. CONCLUSION Thus, we confirmed that the numerical value of TBR max is a relative indicator. And when interpreting PET data, we cannot rely only on the TBR max value in the range from 1.7 to 2.8 for a confident judgment about the genesis of increased RP uptake in tumors. In the absence of other markers of the development of progression (for example, the appearance of new pathological foci), to assess the dynamics and confidently identify post-radiation changes, a repeat PET study should be prescribed after 2-3 months with a preliminary MRI with contrast enhancement.